Irbesartan, which is chemically 2-n-butyl-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1.3-diazaspiro[4.4]non-1-en-4-one (3) is an antagonist of angiotensin-II receptors and acts as an antihypertensic. The compound prepared according to U.S. Pat. No. 5,270,317 is polymorph A and crystallizes in the habit of stable and non-hygroscopic needles, which can be stored and incorporated into pharmaceutical formulations without any decomposition. During the synthesis it is convenient to prepare irbesartan from its protected derivative, e.g. from 2-butyl-3-[[2′-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1′-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (1). The deprotection reaction normally results in a mixture or irbesartan and triphenylmethanole or other compound formed from protecting group that both exhibit similar solubilities in variety of solvents and are thus hard to separate by conventional means.
An approach, known for deprotection of structurally similar trityl losartan, to prepare a potassium salt, which could be separated due its solubility in aqueous media, is not feasible, because an attempt to convert irbesartan to potassium salt by KOH results in degradation, to which the spiro system of irbesartan is sensitive in alkaline media.
None of the disclosures of preparation of irbesartan address the purification thereof via hydrohalide acid addition salts. Thus WO 04/007482 teaches the acidification to pH 2-3.5 of trityl irbesartan, which is sufficient to remove the protecting group, but not to convert into an acid addition salt; WO 04/065383 is likewise silent on hydrohalide acid addition salts. WO 06/011859 relates to the preparation of a hydrochloride salt of irbesartan in order to incorporate it into a pharmaceutical formulation. WO99/38847 mentions optional conversion of irbesartan into hydrochloride, hydrobromide or hydrogen sulfate salts. No specific hydrobromide salt of irbesartan has however yet been isolated nor any advantage of any specific crystalline hydrobromide salt has been postulated.